Cellulose derivatives are industrially important and are used in a large variety of technology areas and in many different end-use applications, for example in the personal care or pharmaceutical industry, in agricultural applications, and in the building or oil industry. Their preparation, properties and applications are described, for example, in Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition, (1986), Volume A5, pages 461-488, VCH Verlagsgesellschaft, Weinheim or in “Methoden der organischen Chemie” (methods of organic chemistry), 4th Edition (1987), Volume E20, Makromolekulare Stoffe, Part Volume 3, pages 2048-2076, Georg Thieme Verlag, Stuttgart.
Water-soluble cellulose derivatives have found wide-spread use. These water-soluble cellulose derivatives are conveniently supplied as a particulate dry material that is then dissolved in water for the desired end use of such water-soluble cellulose derivatives. Unfortunately, some water-soluble cellulose derivatives are difficult to dissolve in water due to the fact that the first particles that come into contact with water immediately swell and stick to each other, forming a gel-like barrier that shields the remaining particles from hydration. The above-described gel-blocking behavior of water-soluble cellulose derivatives is a considerable drawback for those applications of water-soluble cellulose derivatives that comprise the solution of the particulate water-soluble cellulose derivatives such as cellulose ethers in aqueous systems. The gel blocking behavior is visible as the formation of “lumps” which require a long time for complete dissolution. To overcome this gel blocking behavior or the formation of lumps the cellulose derivatives are dispersed in hot water, typically above about 80° C. During agitation the dispersion is cooled and dissolution of the cellulose derivative takes place. At a specific temperature the cellulose derivative starts to dissolve and to build up viscosity. Characteristic temperatures that describe the dissolution behavior are the onset dissolution temperature and the temperature at which the maximum of the dissolution rate is reached. This so-called hot/cold water dissolution technique takes advantage of the fact that water-soluble cellulose derivatives such as cellulose ethers are generally insoluble in hot water and soluble in cold water, depending on the type and degree of substitution. Unfortunately, this hot/cold water dissolution technique is quite time-consuming for those who have to prepare aqueous solutions of the cellulose derivatives. Providing water-soluble cellulose derivatives with a high onset dissolution temperature would be highly desirable since less cooling of the hot dispersions of the water-soluble cellulose derivative would be required to dissolve the cellulose derivative in water.
Another important use of cellulose derivatives, particularly water-soluble cellulose derivatives, is their incorporation as excipients in sustained release dosage forms. Sustained release dosage forms are designed to release a finite quantity of a compound into an aqueous environment over an extended period of time. Known sustained release pharmaceutical dosage forms contain a medicament or a vitamin whose rate of release is controlled by a polymeric matrix. Sustained release pharmaceutical dosage forms are desirable because they provide a method of delivering a long-lasting dose in a single application without overdosing. U.S. Pat. No. 4,734,285 discloses that the release of an active composition from a solid tablet can be prolonged by employing a fine particle sized hydroxypropyl methylcellulose ether composition as an excipient in the solid tablet. The particle size of the hydroxypropyl methylcellulose ether is so small that at least 90 percent by weight of the cellulose ether particles pass through a 100 mesh screen (149 micrometers mesh size), and preferably at least 97 percent by weight of the cellulose ether particles pass through a 140 mesh screen (105 micrometers mesh size) to achieve a long release profile. While such hydroxypropyl methylcellulose ether particles provide excellent release profiles to tablets, these particles of very small size are known to have poor flow properties. A poor flowability of the cellulose ether particles can lead to problems in the manufacturing of dosage forms such as tablets. Problems can include increased variability in tablet weight or tablet crushing strength from tablet-to-tablet as well as variation in the amount of active ingredient incorporated into each dosage form. Poor particle flow can also lead to consolidation of the powder bed in processing equipment, such as storage bins and tablet press feed hoppers.
The International Patent Application Publication No. WO 2008/127794 addresses the poor flowability of the hydroxypropyl methylcellulose ether disclosed in U.S. Pat. No. 4,734,285. WO 2008/127794 discloses a granular material having a mean particle diameter of 150 to 800 micrometers and an untapped bulk density of 0.1 to 0.35 g/cm3, the main component of the granular material being a cellulose derivative. The granular material is a useful excipient for sustained-release dosage forms, particularly for excipients to be used in a direct compression process, due to the good flow and the good compactibility of the granular material leading to strong, hard tablets, with small variability in tablet-to-tablet physical properties, in combination with reproducible kinetics of the sustained release of the active ingredient. Unfortunately, it has been found that the low density of the granular material may cause some problems when blending the granular material with the active ingredient. Due to the low density of the granular material, the weight of the blend of granular material and active material in the blender typically has to be reduced to avoid overfilling of the blender, which reduces the throughput through the blender. Also, formulators may need to pre-compress the blend of granular material and active ingredient to be able to fill tablet dies with the target tablet weight.
Accordingly, it would be highly desirable to provide cellulose derivatives which have a good flowability in combination with a reasonably high untapped bulk density.
Accordingly, the object of the present invention is to find a way of increasing the flowability or the onset dissolution temperature of cellulose derivatives in particulate form. A preferred object of the present invention is to find a way of increasing the flowability and the onset dissolution temperature of cellulose derivatives in particulate form. Another preferred object of the present invention is to find a way of increasing the flowability and/or the onset dissolution temperature of cellulose derivatives in particulate form in such a manner that the particulate cellulose derivates have a reasonably high untapped bulk density.
Surprisingly, it has been found that the flowability and/or the onset dissolution temperature of cellulose derivatives in particulate form can be increased in a novel process for grinding and drying a moist cellulose derivative. Several processes for drying-grinding moist cellulose derivatives are known in the art, such as described in the patent applications GB 2 262 527 A; EP 0 824 107 A2; EP-B 0 370 447 (equivalent to U.S. Pat. No. 4,979,681); WO 96/00748 A1; EP 1 127 895 A1 (equivalent to US 2001/034441) and EP 0 954 536 A1 (equivalent to U.S. Pat. No. 6,320,043), but none of these references addresses the problem of increasing the onset dissolution temperature of cellulose derivatives in particulate form or provide an evidence of good flowability of the cellulose derivatives.